Fosfomycin - IV

Fosfomycin - IV belongs to the pharmacological class of Phosphonics Derivatives

Fosfomycin - IV has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Bone and joint infection, Endocarditis, infective, Intra-abdominal infection, complicated, Meningitis, bacterial, Pneumonia, hospital-acquired or ventilator-associated, Prostatitis, chronic bacterial, Skin and soft tissue infection, complicated, Urinary tract infection.

Fosfomycin, a hydrophilic drug with a low molecular weight, demonstrates rapid absorption in the small intestine when taken orally, leading to its distribution throughout various tissues in the body. Its oral bioavailability typically falls within the range of 34% to 58%. However, co-administration of fosfomycin with food can reduce its gastrointestinal absorption to approximately 30%. Notably, the reported area under the curve (AUC) ranges from 145 to 228 mg x h/L, while the reported maximum concentration (Cmax) is 26.1 (±9.1) mcg/mL.Regarding its volume of distribution, fosfomycin generally exhibits a Vd of around 0.3 L/kg in healthy individuals. Nevertheless, critically ill patients may experience an increased Vd of up to 50% due to alterations in the vascular endothelium. Fosfomycin does not bind significantly to plasma proteins, indicating a lack of substantial protein binding. In terms of metabolism, fosfomycin undergoes minimal to no metabolic transformations and is primarily excreted unchanged in the urine.Renal excretion serves as the primary route for eliminating fosfomycin from the body. However, several factors can influence the rate of elimination, such as the concurrent intake of food, impaired renal function, and advanced age, all of which may result in a decreased clearance of fosfomycin.

The common side effects involved in using Fosfomycin - IV are Nausea, Upset stomach, Stomach pain , Diarrhea, Headache, Dizziness, Weakness, Rash, Sore throat, Runny nose, Back pain, Menstrual pain, Vaginal itching .

Fosfomycin - IV is available in the form of Intravenous injection.

Fosfomycin - IV is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Fosfomycin - IV belongs to the pharmacological class of Phosphonics Derivatives

Fosfomycin tromethamine is a phosphonic acid derivative that exists as the mono-acid salt of fosfomycin combined with tromethamine. At therapeutic doses, fosfomycin exhibits bactericidal activity, specifically within the urinary tract. Its bactericidal effect is achieved by inactivating the enzyme enolpyruvyl transferase, which disrupts the condensation process between uridine diphosphate-N-acetylglucosamine and p-enolpyruvate, an early stage in bacterial cell synthesis. Additionally, fosfomycin helps decrease the adherence of bacteria to uroepithelial cells.

Fosfomycin - IV has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Bone and joint infection, Endocarditis, infective, Intra-abdominal infection, complicated, Meningitis, bacterial, Pneumonia, hospital-acquired or ventilator-associated, Prostatitis, chronic bacterial, Skin and soft tissue infection, complicated, Urinary tract infection.

The reported area under the curve (AUC) ranges from 145 to 228 mg x h/L, whereas the reported maximum concentration (Cmax) is 26.1 (±9.1) mcg/mL.

Fosfomycin - IV is found to be available in the form of Intravenous injection.

Fosfomycin - IV can be used in the following treatment:

• Bloodstream infection
• Bone and joint infection
• Endocarditis, infective
• Intra-abdominal infection, complicated
• Meningitis, bacterial
• Pneumonia, hospital-acquired or ventilator-associated
• Prostatitis, chronic bacterial
• Skin and soft tissue infection, complicated
• Urinary tract infection

Fosfomycin - IV can help to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Bone and joint infection, Endocarditis, infective, Intra-abdominal infection, complicated, Meningitis, bacterial, Pneumonia, hospital-acquired or ventilator-associated, Prostatitis, chronic bacterial, Skin and soft tissue infection, complicated, Urinary tract infection.

Fosfomycin - IV is approved for use in the following clinical indications:

• Bloodstream infection
• Bone and joint infection
• Endocarditis, infective
• Intra-abdominal infection, complicated
• Meningitis, bacterial
• Pneumonia, hospital-acquired or ventilator-associated
• Prostatitis, chronic bacterial
• Skin and soft tissue infection, complicated
• Urinary tract infection

• Bloodstream Infection:

IV: Administer 12 to 24 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose. High-dose regimens (>16 g/day) should be reserved for severe infections caused by organisms with decreased susceptibility to fosfomycin.

• Bone and Joint Infection:

IV: Administer 12 to 24 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose. High-dose regimens (>16 g/day) should be reserved for severe infections caused by organisms with decreased susceptibility to fosfomycin.

• Infective Endocarditis:

IV: Administer 12 to 24 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose. High-dose regimens (>16 g/day) should be reserved for severe infections caused by organisms with decreased susceptibility to fosfomycin.

• Complicated Intra-abdominal Infection:

IV: Administer 12 to 24 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose. High-dose regimens (>16 g/day) should be reserved for severe infections caused by organisms with decreased susceptibility to fosfomycin.

• Bacterial Meningitis:

IV: Administer 16 to 24 g/day in 3 to 4 divided doses, with a maximum dose of 8 g per dose. High-dose regimens (>16 g/day) should be reserved for severe infections caused by organisms with decreased susceptibility to fosfomycin.

• Hospital-Acquired or Ventilator-Associated Pneumonia:

IV: Administer 12 to 24 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose. High-dose regimens (>16 g/day) should be reserved for severe infections caused by organisms with decreased susceptibility to fosfomycin.

• Chronic Bacterial Prostatitis (Alternative Agent):

Note: Fosfomycin should be reserved for use when other options are not appropriate due to resistance or intolerance. The optimal dosing has not been established. Some suggested dosing regimens include oral administration of 3 g every 2 to 3 days or 3 g once daily for 1 week, followed by 3 g once every 48 hours. The duration of treatment should be at least 6 weeks.

• Complicated Skin and Soft Tissue Infection:

IV: Administer 12 to 24 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose. High-dose regimens (>16 g/day) should be reserved for severe infections caused by organisms with decreased susceptibility to fosfomycin.

Urinary Tract Infection:

• Asymptomatic Bacteriuria in Pregnancy: Administer 3 g as a single dose.
• Acute Uncomplicated or Acute Simple Cystitis: Administer 3 g as a single dose. Multidose regimens have been described, but their efficacy compared to single-dose therapy is unknown.
• Prophylaxis for Recurrent Cystitis (Alternative Agent): Consider for nonpregnant women with bothersome, frequently recurrent cystitis. Duration ranges from 3 to 12 months, with periodic reassessment. Continuous prophylaxis can be achieved with 3 g orally once every 7 to 10 days.
• Complicated Urinary Tract Infection (including Pyelonephritis): IV : Administer 12 to 24 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose. Duration of therapy varies from 5 to 14 days, based on clinical response and the chosen antimicrobial agent to complete the regimen.

Intravenous injection: 1g, 2g, 4g and 500mg.

Intravenous injection.

• Dosage Adjustments in Kidney Patients:

In patients with varying degrees of renal impairment (creatinine clearance ranging from 54.2 mL/min to 7.3 mL/min), the half-life of fosfomycin has been observed to increase. Therefore, physicians should carefully assess whether the potential benefits of using the drug outweigh the potential risks for patients with severe renal impairment or those undergoing hemodialysis.

Dosage Adjustments in Pediatric Patients:

• Urinary Tract Infection, Uncomplicated:

High-dose regimens (>300 mg/kg/day for ≤40 kg and >16 g/day for >40 kg) may be considered. However, data is limited for doses exceeding 16 g/day, so close monitoring is advised.

• Bacterial Meningitis:

Infants, Children, and Adolescents: IV:

• Less than 10 kg: Administer 200 to 300 mg/kg/day in 3 divided doses.
• 10 to 40 kg: Administer 200 to 400 mg/kg/day in 3 to 4 divided doses.
• Over 40 kg: Administer 16 to 24 g/day in 3 to 4 divided doses, with a maximum dose of 8 g per dose.
• Osteomyelitis:

Infants, Children, and Adolescents: IV:

• Less than 10 kg: Administer 200 to 300 mg/kg/day in 3 divided doses.
• 10 to 40 kg: Administer 200 to 400 mg/kg/day in 3 to 4 divided doses.
• Over 40 kg: Administer 12 to 24 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose.
• Nosocomial Lower Respiratory Tract Infection:

Infants, Children, and Adolescents: IV:

• Less than 10 kg: Administer 200 to 300 mg/kg/day in 3 divided doses.
• 10 to 40 kg: Administer 200 to 400 mg/kg/day in 3 to 4 divided doses.
• Over 40 kg: Administer 12 to 24 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose.
• Complicated Urinary Tract Infection:

Infants, Children, and Adolescents: IV:

• Less than 10 kg: Administer 200 to 300 mg/kg/day in 3 divided doses.
• 10 to 40 kg: Administer 200 to 400 mg/kg/day in 3 to 4 divided doses.

• Over 40 kg: Administer 12 to 16 g/day in 2 to 3 divided doses, with a maximum dose of 8 g per dose.

Fosfomycin IV does not have specific dietary restrictions. However, it is generally recommended to follow a balanced and healthy diet while undergoing treatment with fosfomycin IV. It is important to maintain adequate hydration by drinking plenty of fluids.

Fosfomycin - IV may be contraindicated under the following conditions:

• Fosfomycin - IV is contraindicated in patients who have demonstrated hypersensitivity to the drug.

• Driving and Operating Machinery

Although no specific studies have been conducted to assess the effects of Fosfomycin _IV® (fosfomycin tromethamine) on driving and operating machinery, it has been reported that some patients experience dizziness while taking this medication. This dizziness may affect the ability of certain patients to drive or operate machinery. It is important to exercise caution when engaging in activities that require alertness and concentration, such as driving or operating potentially dangerous machinery.

• Route of Administration, Dosage Form, and Non-medicinal Ingredients

Fosfomycin _IV is administered orally and is available as a powder for solution, with each sachet containing 3g of fosfomycin tromethamine. The formulation includes mandarin and orange flavorings (containing sulfites), saccharin, and sucrose.

• Gastrointestinal: Clostridium difficile-associated disease

The use of fosfomycin tromethamine, like many other antibacterial agents, has been associated with the development of Clostridium difficile-associated disease (CDAD). CDAD can range in severity from mild diarrhea to life-threatening colitis. Patients presenting with symptoms such as diarrhea, colitis, pseudomembranous colitis, toxic megacolon, or colon perforation after receiving antibacterial treatment should be evaluated for CDAD. CDAD can occur up to 2 months after antibacterial administration. Disruption of the normal colon flora by antibacterial agents may lead to overgrowth of Clostridium difficile, which produces toxins contributing to CDAD. Treatment for CDAD should be initiated if suspected or confirmed. Mild cases may respond to discontinuation of antibacterial agents not effective against C. difficile, while moderate to severe cases may require fluid and electrolyte management, protein supplementation, and treatment with a suitable antibacterial agent. Drugs that inhibit intestinal movement should not be used for CDAD treatment, as they may delay the clearance of C. difficile and its toxins. Surgical evaluation may be necessary in severe cases.

• Genitourinary: Persistent infections

In cases of persistent infections, it is recommended to conduct a thorough examination and re-evaluate the diagnosis. Persistent infections may be caused by complicated urinary tract infections or the presence of resistant pathogens. Please refer to the Susceptibility/Resistance section for additional information.

• Immune: Hypersensitivity reactions

Hypersensitivity reactions, including life-threatening anaphylaxis and anaphylactic shock, have been reported during treatment with Fosfomycin _IV. Fosfomycin _IV also contains sulfites, which in rare cases, may cause severe hypersensitivity and bronchospasm. If any such reactions occur, immediate medical treatment is necessary, and Fosfomycin _IV should not be re-administered.

• Renal: Impact on patients with renal impairment

In patients with varying degrees of renal impairment (creatinine clearance ranging from 54.2 mL/min to 7.3 mL/min), the half-life of fosfomycin has been observed to increase. Therefore, physicians should carefully assess whether the potential benefits of using the drug outweigh the potential risks for patients with severe renal impairment or those undergoing hemodialysis.

• It is important to exercise caution and avoid consuming alcohol while taking fosfomycin. Alcohol may interact with fosfomycin and potentially lead to adverse effects or reduce the effectiveness of the medication.
• Drinking alcohol while on fosfomycin treatment can increase the risk of side effects such as nausea, vomiting, dizziness, and gastrointestinal disturbances. Additionally, alcohol consumption can impair liver function, which may impact the body's ability to metabolize and eliminate fosfomycin effectively.

Fosfomycin is present in human milk in minimal amounts. Currently, there is no available information regarding the impact of fosfomycin on breastfed infants or milk production.

Pregnancy:

Teratogenic Effects - Category B

Fosfomycin has the ability to pass through the placental barrier, but its safety for treating infections during pregnancy has not been determined. The use of Fosfomycin - IV should be avoided during pregnancy unless it is clearly necessary and the potential benefits to the mother outweigh the potential risks to the fetus.

The presence of food in the stomach can slow down the absorption of Fosfomycin - IV, leading to a reduction in both peak plasma levels and urinary concentrations of the medication. For this reason, it is advised to take Fosfomycin - IV on an empty stomach or, if necessary, wait for at least 2-3 hours after a meal before administration.

By avoiding concurrent intake of Fosfomycin - IV with food, the medication can be absorbed more efficiently, ensuring optimal effectiveness in the treatment of the infection. Following these recommendations and taking Fosfomycin - IV on an empty stomach or with a sufficient time gap after a meal can help maximize its absorption and therapeutic benefits.

The adverse reactions related to Fosfomycin - IV can be categorized as follows:

Common:

• Itching sensation in the vagina or genital area.
• Discomfort or itching during sexual intercourse.
• Presence of thick, white vaginal discharge with either no odor or a mild odor.

Less Common:

• Acidic or sour stomach.
• Belching.
• Indigestion.
• Heartburn.
• Stomach discomfort or upset.
• Excess air or gas in the stomach or intestines.
• Back pain.
• Body aches or pain.
• Joint pain.
• Muscle aching or cramping.
• Congestion.
• Dryness or soreness of the throat.
• Runny or stuffy nose.
• Sneezing.
• Sore throat.
• Trouble with swallowing.
• Voice changes.
• Heavy bleeding.
• Lack or loss of strength.
• Painful menstruation.
• Skin rash.
• Tender, swollen glands in the neck.
• Dry mouth.
• Nervousness.
• Passing gas.
• Sleepiness or unusual drowsiness.
• Headache (severe and throbbing).
• Loss of appetite.
• Full feeling.

Rare:

• Blurred vision.
• Decreased vision.
• Eye pain.
• Blue-yellow color blindness.
• Visual impairment or blindness.
• Abnormal stools.
• Absent, missed, or irregular menstrual periods.
• Full feeling.
• Headache (severe and throbbing).
• Loss of appetite.
• Passing gas.
• Sleepiness or unusual drowsiness
• Burning, crawling, itching, numbness, prickling, "pins and needles," or tingling sensations.
• Difficulty with moving.
• Nervousness.

Metoclopramide and its Impact on Fosfomycin Concentrations:

• When administered together with Fosfomycin - IV, metoclopramide, a drug that enhances gastrointestinal motility, reduces the serum concentration and urinary excretion of fosfomycin.
• Similar effects may be observed with other drugs that increase gastrointestinal motility.

Probenecid and its Interaction with Fosfomycin:

• Probenecid should not be prescribed concurrently with Fosfomycin - IV, as it has been demonstrated to significantly decrease renal clearance and excretion of fosfomycin.
• In healthy volunteers receiving an infusion of disodium fosfomycin, probenecid caused a notable decrease in renal clearance, possibly by inhibiting tubular secretion, leading to lower urinary concentrations.

Absence of Therapeutic Assessments:

• No evaluations have been conducted to assess the effects of metoclopramide or probenecid on urinary levels of fosfomycin in women with acute urinary tract infection following their administration with Fosfomycin - IV.
• Based on data from healthy volunteers, urinary levels of fosfomycin may not reach bactericidal levels for a sufficient duration to achieve microbiological cure.
• It is not recommended to co-prescribe Fosfomycin - IV with either of these drugs.

Cimetidine and its Interaction with Fosfomycin:

• Co-administration of cimetidine with Fosfomycin - IV does not impact the pharmacokinetics or urinary concentrations of fosfomycin.

The following are the side effects involving Fosfomycin - IV:

• Nausea
• Upset stomach
• Stomach pain
• Diarrhea
• Headache
• Dizziness
• Weakness
• Rash
• Sore throat
• Runny nose
• Back pain
• Menstrual pain
• Vaginal itching
• Vaginal discharge

Pregnancy:

Teratogenic Effects - Category B

Fosfomycin has the ability to pass through the placental barrier, but its safety for treating infections during pregnancy has not been determined. The use of Fosfomycin - IV should be avoided during pregnancy unless it is clearly necessary and the potential benefits to the mother outweigh the potential risks to the fetus.

Lactation:

Fosfomycin is present in human milk in minimal amounts. Currently, there is no available information regarding the impact of fosfomycin on breastfed infants or milk production.

Pediatric:

Pediatrics (<12 years):

Health Canada has authorized the use of Fosfomycin - IV (fosfomycin for injection) in pediatric patients based on the available limited data that was submitted and reviewed. The safety and efficacy of fosfomycin in pediatric patients have been established. However, it is important to note that the safety and efficacy of fosfomycin in neonates and children with renal impairment have not been specifically evaluated in clinical trials

Geriatric Use:

Dose adjustment solely based on age is not required. However, it is important to evaluate renal function, and if there are indications of renal impairment, the dose should be decreased.In the geriatric population (aged >65 years), no disparity in drug efficacy or tolerance was observed when compared to patients below 65 years of age. However, caution should be exercised when considering the use of doses towards the upper limit of the recommended range.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Fosfomycin - IV.

• Limited Experience with Overdose:
• There is limited information available regarding overdose with Fosfomycin - IV (fosfomycin for injection).
• Reported cases of overdose have shown symptoms such as hypotonia, somnolence, electrolyte disturbances (including hypernatremia, hypokalemia, hypophosphatemia), thrombocytopenia, and hypoprothrombinemia.

Monitoring and Treatment:

• In the event of an overdose, close monitoring of the patient is necessary, especially regarding plasma/serum electrolyte levels.
• Treatment should be symptomatic and supportive, addressing the specific symptoms or complications that arise.
• Rehydration is recommended to facilitate urinary elimination of the drug.

Hemodialysis:

• Fosfomycin can be effectively cleared from the body through hemodialysis.
• Hemodialysis has a mean elimination half-life of approximately 4 hours for fosfomycin.

Pharmacodynamics:

Fosfomycin, primarily used for treating urinary tract infections, has shown synergistic effects when combined with other antibiotics against clinically relevant bacteria. Additionally, there is increasing interest in its potential to address more complex infections, as it remains effective against many difficult-to-treat strains, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant enterobacteria. Moreover, due to its unique mechanism of action, the risk of developing cross-resistance with other antibiotics is low.

Furthermore, fosfomycin exhibits immunomodulating properties. For instance, it can influence components of the acute inflammatory cytokine response and enhance neutrophil phagocytic destruction of pathogens.

Fosfomycin demonstrates effective penetration of biofilms, enabling it not only to reduce or eliminate microorganisms within biofilms but also to modify the structure of the biofilm itself.

Pharmacokinetics:

Serum Concentrations and Half-Life:

● Intravenous infusion of 4 g and 8 g of fosfomycin in young, healthy males resulted in maximum serum concentrations (Cmax) of approximately 200 μg/mL and 400 μg/mL, respectively.

● The serum half-life was approximately 2 hours.

● In elderly and/or critically ill male and female subjects, a single intravenous dose of 8 g of fosfomycin resulted in mean Cmax of approximately 350-380 μg/mL and plasma half-lives of 3.6-3.8 hours.

Pharmacokinetic Behavior:

● Fosfomycin exhibits linear pharmacokinetic behavior after intravenous infusion of therapeutically used doses.

Distribution:

● The apparent volume of distribution of fosfomycin is approximately 0.30 L/kg body weight.

● Fosfomycin is well-distributed in tissues, including eyes, bones, wound secretions, musculature, cutis, subcutis, lungs, and bile.

● In patients with inflamed meninges, cerebrospinal fluid concentrations reach about 20-50% of corresponding serum levels.

● Fosfomycin crosses the placental barrier, and low quantities are found in human milk (about 8% of serum concentrations).

● The plasma protein binding of fosfomycin is negligible.

Metabolism:

● Fosfomycin is not metabolized by the liver and does not undergo enterohepatic circulation.

● No accumulation is expected in patients with hepatic impairment.

Elimination:

● In healthy adults, 80-90% of the administered dose of Fosfomycin - IV (fosfomycin for injection) is eliminated renally within 10 hours after a single intravenous administration.

● Fosfomycin is not metabolized, and the biologically active compound is eliminated.

● In patients with normal or mildly to moderately impaired renal function (creatinine clearance ≥ 40 mL/min), approximately 50-60% of the overall dose is excreted within the first 3-4 hours.

• "First-trimester pregnancy exposure to fosfomycin and the risk of a major congenital anomaly: a comparative study using the EFEMERIS database" by Benevent J, Araujo M, Beau AB, et al. was published in Infection in 2023. It has the PubMed ID 35689790 and DOI 10.1007/s15010-022-01861-4.
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